Levothyroxine, also L-thyroxine or T4, is a synthetic form of the thyroid hormone thyroxine, which is normally secreted by the follicular cells of the thyroid gland. Thyroid hormone increases the metabolic rate of cells of all tissues in the body. In the fetus and newborn, thyroid hormone is important for the growth and development of all tissues including bones and the brain. In adults, thyroid hormone helps to maintain brain function, utilization of food, and body temperature, among other effects.
Levothyroxine Sodium contain synthetic crystalline L-3,3′,5,5′-tetraiodothyronine sodium salt [Levothyroxine (T4) sodium]. O-(4-hydroxy-3,5-diiodo-phenyl)-3,5-diiodo-1-tyrosine sodium i.e., Levothyroxine sodium has the following chemical structure

Levothyroxine sodium is approved to treat hypothyroidism to suppress thyroid hormone release from cancerous thyroid nodules, and to prevent growth of goiters. In addition, it is also used to treat conditions such as myoedema, cretinism and obesity.
J Chem. Soc, (1949); 3424-33 describes a process for the synthesis of mono sodium salt of Levothyroxine comprising the steps of: (a) nitration of Levo tyrosine; (b) protection of the amino group; c) protection of the carboxy group; (d) oxidative coupling; (e) hydrogenation of the nitro groups to amino groups; (f) diazotization followed by iodination; (g) demethylation of the Me ether and hydrolysis; (h) which on iodination in presence of iodine to obtain Levothyroxine, which is further converted in to Levothyroxine sodium.
IT 1302201 disclosed a process for the synthesis of mono sodium salt of Levothyroxine with an improved overall yield compared to a similar process disclosed in J Chem. Soc, (1949) 3424-33. IT 1302201 discloses a process for preparing Levothyroxine comprising reacting 3,5 diiodo-L-thyronine with iodine and potassium iodide.
Journal of the Chemical Society, 840-3; 1950, discloses a process for the preparation of Levothyroxine comprising reacting 3,5 diiodo L-thyronine with KI3 in water and ethylamine.
U.S. Pat. No. 2,579,668 discloses a process for the preparation of Levothyroxine comprising reacting 3,5 diiodo-L-thyronine with iodine in a solvent selected from water, dioxane, lower aliphatic alcohols and mixtures thereof, in the presence of an organic base selected from the group consisting of piperidine, morpholine and amines.
U.S. Pat. No. 2,886,592 discloses a process for the preparation of Levothyroxine comprising reacting 3,5 diiodo-L-thyronine with N-iodoacetamide in absolute methanol in presence of triethylamine.
Vestsi Natsyyanal'nai Akademii Navuk Belarusi, Seryya Khimichnykh Navuk, (1), 85-92; 2004 discloses a process for the preparation of Levothyroxine comprising reacting 3,5 diiodo L-thyronine with iodine & potassium iodide in water & methanol in presence of ammonia.
WO 2009136249 discloses a process for the preparation of Levothyroxine comprising reacting 3,5-diiodo-4-p-hydroxy phenoxy-L-phenyl alanine hydrochloride with methyl amine and Iodine source such as iodine and/or potassium iodide.
US 20120296113 discloses a process for the synthesis of mono sodium salt of Levothyroxine comprising reacting 3,5 diiodo-L-thyronine with an iodinating agent such as NaI & I2, in the presence of an aliphatic amine.
These above mentioned processes have number of disadvantages such as
(a) use of highly expensive iodinating agent like iodine, potassium iodide, KI3, N-iodoacetamide and sodium iodide.
(b) the use of high amount of iodinating agent such as iodine, potassium iodide, KI3, N-iodoacetamide and sodium iodide for iodination is not recommendable at commercial scale,
(c) yield of above reactions is very less that makes the process less effective from an economic point of view.
In view of problems in commercialization of process for the preparation of Levothyroxine and its salts, there is a need for simple, cost effective, commercially feasible, industrially scalable and environmentally friendly process for the preparation of Levothyroxine and its salts with high purity and yield.
The iodinating agent plays a crucial role in multi-step synthesis of organic molecule like Levothyroxine having variety of functional groups. Surprisingly, it has been found that if sodium iodide & sodium hypochlorite is used in the desired iodination step, the yield of iodination reaction is good. Another advantages is both sodium iodide & sodium hypochlorite are cheaper than any other iodinating agent which results in significant cost savings compared to the other known process.
The object of the present invention is to provide an industrially advantageous process for the preparation of Levothyroxine and its salts with overall high yield and purity.